NON SOLUS
ELSEVIER
Available online at www.sciencedirect.com ScienceDirect
journal homepage: www.elsevier.com/locate/radcr
RCR RADIOLOGY CASE REPORTS
Case report
Non-functioning adrenocortical carcinoma
Bui-Van Lenh, MD, PhDa,b,1, Nguyen Minh Duc, MD, MScb,c,d,1,*, Thieu-Thi Tra My, MDb, Tran Ngoc Minh, MDe, Luong Viet Bang, MDf, Le Tuan Linh, MD, PhDa,b, Bui-Van Giang, MD, PhDb, Pham Minh Thong, MD, PhDb
ª Department of Radiology, Hanoi University Medical Hospital, Hanoi, Vietnam
b Department of Radiology, Hanoi Medical University, Hanoi, Vietnam
“Department of Radiology, Pham Ngoc Thach University of Medicine, Ho Chi Minh City, Vietnam
d Department of Radiology, Children’s Hospital 2, Ho Chi Minh City, Vietnam
e Department of Pathology, Hanoi Medical University Hospital, Hanoi, Vietnam f Department of Pathology, Tam Anh General Hospital, Hanoi, Vietnam
ARTICLE INFO
Article history: Received 28 February 2021 Accepted 8 March 2021
Keywords: Adrenal tumor Adrenocortical carcinoma Rare neoplasm
ABSTRACT
Adrenocortical carcinoma (ACC) is a rare malignancy that arises from the adrenal cortex and can be classified as either non-functioning or functioning. A patient with non-functioning ACC may present no specific symptoms. Imaging analysis can provide some information to a clinician who suspects ACC, such as tumor size, density, washout, necrosis, hemorrhage, and calcification. Histopathology is used to confirm and determine the origin of the malig- nancy and can provide relevant prognostic information. Microscopic findings can be used to obtain information such as the Weiss score, resection surface features, Ki-67 prolifera- tive index, and the degree of capsular and vascular invasion. Surgery can be curative for localized tumors, and adjuvant therapy using mitotane and cytotoxic chemotherapy is of- ten employed for advanced-stage tumors. We describe a case report of a 32-year-old man with a non-functioning ACC that highlights the importance of radiological and pathological features in the diagnosis of ACC and their use as prognostic factors.
@ 2021 The Authors. Published by Elsevier Inc. on behalf of University of Washington. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/)
Introduction
Adrenocortical carcinoma (ACC) is a rare and aggressive en- docrine malignancy that originates from the adrenal cortex
and is associated with a dismal prognosis [1]. The estimated incidence of ACC is 0.5-2 cases per million population each year [2]. ACC can be classified as either functioning (which re- sults in the production of a higher than normal hormone con-
# Acknowledgements: Self-financed.
** Competing interests: The authors do not report any conflicts of interest.
* Corresponding author. 2 Duong Quang Trung, Ward 12, District 10, Ho Chi Minh City, Vietnam E-mail address: bsnguyenminhduc@pnt.edu.vn (N.M. Duc).
1 Two authors contributed equally to this article as co-first authors. https://doi.org/10.1016/j.radcr.2021.03.006
1930-0433/ 2021 The Authors. Published by Elsevier Inc. on behalf of University of Washington. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/)
O -18HU
O 60HU
centration level) or non-functioning (which results in the pro- duction of manufacturing a lower than normal hormone con- centration level). Functioning tumors are more common than non-functioning tumors [3]. ACC can present with symptoms consistent with excess hormone secretion or as an abdominal mass, or ACC can be discovered incidentally during the course of investigating other clinical issues [4]. Imaging plays impor- tant roles in the identification and characterization of ACC, the determination of a malignancy risk, staging evaluation, and follow-up [5]. Histological and immunohistochemical fea- tures can be used to confirm the identity of an adrenocortical tumor, provide advanced knowledge that can be used to de- termine prognosis, and guide the application of appropriate therapeutic options for these infrequent neoplasms [6].
Case report
A 32-year-old male with a normal medical history presented with left, upper-quadrant, dull pain for 1 month. An abdomi- nal examination revealed a large mass located in the left up- per quadrant. An abdominal computed tomography (CT) scan was performed. On the pre-contrast phase CT, a large mass was identified, situated in the left adrenal gland, measuring 12 × 12 × 11 cm3. The mass had a heterogeneous density, with an average density of 35 Hounsfield (HU). The lowest density was recorded at -18 HU, whereas the highest density was 60 HU (Fig. 1). On the arterial phase, the mass appeared hyper vascular (Fig. 2A), with heterogeneous enhancement (Fig. 2B). The mass compressed the left kidney (Fig. 2C) and the left re- nal vein, resulting in the dilatation of the left gonadal vein (Fig. 2D). The mass showed a slightly elevated level of en- hancement in the venous phase (Fig. 3). No abnormal lymph nodes were noticed. This mass was suspected to be a malig- nant adrenal mass. The patient’s serum cortisol level was 350 nmol/L, which is within the normal range [7]. The levels of electrolytes in the blood and the blood pressure were normal, and the patient did not present with the symptoms of Cushing
syndrome. The patient underwent total gross tumor resection. Macroscopically, the mass was large and had a thin capsule (Fig. 4). The cut surface showed a heterogeneous mass, with a white to red appearance. An area of hemorrhage was identi- fied, and the adipose tissue presented with a yellow appear- ance. Microscopically, the tumor had a fibrous capsule (Fig. 5A) and a necrotic region (Fig. 5B). The typical patterns associated with adrenal cortical adenomas were replaced by a broad tra- becular appearance and a diffuse architecture, characterized as nuclear grades III and IV, with > 20 mitotic figures/50 high power fields (HPFs, Fig. 5C). No signs of capsular or vascular invasion were observed (Fig. 5A). Atypical mitotic figures were observed (Fig. 5D). The tumor margins were free. Immunohis- tochemical analysis showed that the tumor cells stained pos- itively for calretinin (Fig. 6A) and synaptophysin (Fig. 6B) and negatively for chromogranin (Fig. 7A), Melan A (Fig. 7B), S100 (Fig 7C); the Ki67 index was > 5% (Fig. 7D). This tumor was de- termined to be of adrenal cortical origin, with a Weiss score of five. Thus, the final diagnosis for this patient was ACC. The patient was treated with adjuvant chemotherapy, consisting of ondansetron, cisplatin, and etoposide.
Discussion
Adrenocortical carcinoma is an uncommon disease that can develop at any age. The underlying causes of most ACCs are unknown, but ACC can be associated with hereditary tumor syndromes, such as Li-Fraumeni syndrome, Lynch syndrome, multiple endocrine neoplasia type one, and familial adeno- matous polyposis [8]. Most adrenal tumors are unilateral, al- though bilateral ACC can also occur [9]. A functioning adreno- cortical tumor overproduces the following hormones: cortisol, aldosterone, testosterone, and estrogen. Therefore, function- ing ACCs can present with the symptoms associated with sev- eral different endocrine syndromes, including Cushing’s syn- drome and virilization [10]. In contrast, patients with non- functioning ACC may present with a variety of nonspecific symptoms, such as abdominal pain, fatigue, and symptoms related to mass effects. However, the discovery of asymp- tomatic adrenal masses has become more common due to the development of innovative imaging modalities [11]. The preoperative assessment of basal levels of cortisol, adreno- corticotropic hormone, dehydroepiandrostenedione sulfate, 17-hydroxyprogesterone, testosterone, androstenedione, and estradiol, the performance of a dexamethasone suppression test, and the assessment of urinary free cortisol levels are rec- ommended [3]. These tests may assist in the establishment of the adrenocortical origins of the tumor and provide informa- tion regarding the malignant potential of the tumor. They are also necessary to evaluate the risks of postoperative adrenal insufficiency, and these hormones can serve as tumor mark- ers during postoperative follow-up [12]. Imaging plays a vital role in the diagnosis of ACC. Adrenal tumors with a high risk of malignancy are often characterized by large tumor size (> 4 cm), high density (>10 HU), heterogeneity, absolute washout values below 60%, relative washout values below 40%, necro- sis, hemorrhage, and ossification [3]. On a CT scan, ACC may appear large, with irregular margins, heterogeneity, an average
A
B
C
D
A
B
density > 10 HU, and evidence of calcification, necrosis, and hemorrhage. Approximately 30% of ACC tumors display calci- fication [13]. On CT scans performed with contrast enhance- ment, tumors often display heterogeneous enhancement, typ- ically characterized by the increased enhancement of the pe- ripheral regions compared with the central region due to the presence of necrosis [12]. The identification of invasion, ve- nous thrombus, and lymphadenopathy are clearly suggestive of malignancy. On magnetic resonance imaging (MRI), normal adrenal tissue shows low to intermediate signal intensity on T1- and T2-weighted images [3]. MRI can be useful for deter- mining the lipid contents of a tumor through the use of fat- suppression techniques. MRI can, therefore, be used to sup-
port the differentiation between adrenal adenoma and ACC. On T1-weighted images, ACCs often appear isointense to hy- pointense relative to the normal liver parenchyma, and high signal intensity on T1-weighted images can often be observed due to the presence of hemorrhage [5]. ACCs are hyperintense relative to the normal liver parenchyma on T2-weighted im- ages, with heterogeneous enhancement [5]. MRI can also be used to evaluate the presence of invasion and metastasis in- dicators. Histopathology remains necessary to reach a final and conclusive diagnosis of ACC. Macroscopically, ACCs are typically large and heterogeneous, and the cut surface may appear brown or yellow, depending on the presence of hem- orrhage, necrosis, and lipid contents [14]. Microscopically, the
0
CM 1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
patterns associated with ACC, including solid, broad, nested trabecula, replace the patterns that are typical of adrenal cor- tical adenoma [15]. Thick fibrosis capsules are also associated with carcinoma. Fibrosis brands, tumor necrosis, and hemor- rhage are common features. Tumor invasion of both the cap-
sule and vessels and evidence of mitosis are strong predic- tors of ACC [16]. ACCs express specific markers for steroid- producing cells, such as steroidogenic factor-one, inhibin al- pha, Melan A, and calretinin, which can be detected by im- munohistochemical staining. ACCs are frequently positive for synaptophysin, chromogranin A [17]. Some diagnostic algo- rithms have been used to differentiate benign from malignant adrenocortical tumors, such as the Hough and Weiss systems; however, the Weiss system is the most commonly used sys- tem [14]. Tumors with a Weiss score ≥ 3 are considered ma- lignant, whereas scores of 0-2 define benign tumors [18]. The Weiss system examines nine different items, including nu- clear atypia, atypical mitoses, the mitotic rate, cytoplasmic characteristics, tumor cell architecture, necrosis, invasion of the venous structures, invasion of the sinusoidal structure, and invasion of the tumor capsule [18]. The proliferation in- dex, determined according to the Ki67 immunomarker or mi- totic count, can help to define the diagnosis and prognosis of ACC. ACCs characterized with a Ki67 index value ≥ 5% and a mitotic count > 20 mitoses/50 HPF are associated with poor prognosis [19,20]. Surgery is the first-line therapeutic option, with the potential to cure ACC, and adjuvant mitotane is rec- ommended for patients at high risk for recurrence [3]. More- over, adjuvant chemotherapy, radiation, and targeted thera- pies have also been used to treat ACC [12]. The 5-year survival of ACC patients may reach as high as 77% [4].
A
B
€
D
€
R
A
B
A
B
C
D
In this case report, the patient was diagnosed with a non- functioning ACC, presenting with nonspecific symptoms and a serum cortisol level within the normal range. At the time of diagnosis, imaging revealed a very large tumor, with a hetero- geneous density, including some fat density areas, and an av- erage density greater than 10 HU. These features all suggested a malignant tumor. Histopathology analyses revealed a Ki67 index value >5% and a mitotic count >20 mitoses/50 HPF. To- gether, these imaging and histopathological features support the diagnosis and treatment planning of a malignant ACC.
Conclusion
Adrenocortical carcinoma is an unusual neoplasm that origi- nates from the adrenal cortex. Patients with non-functioning ACC are often diagnosed late, with large masses. CT scans can be useful for characterizing indeterminate adrenal lesions or lesions suspected of malignancy. Histopathological diagnoses associated with the Weiss score and the Ki67 index can sup- port both treatment and prognosis.
Patient consent
Appropriate written informed consent was obtained for the publication of this case report and accompanying images.
Authors’ contributions
Bui-Van L and Nguyen MD contributed to this article as co- first authors. All authors have read the manuscript and agree to the contents.
REFERENCES
[1] Kostiainen I, Hakaste L, Kejo P, Parviainen H, Laine T, Löyttyniemi E, et al. Adrenocortical carcinoma: presentation and outcome of a contemporary patient series. Endocrine 2019;65(1):166-74.
[2] Kerkhofs TMA, Verhoeven RHA, Van der Zwan JM, Dieleman J, Kerstens MN, Links TP, et al. Adrenocortical carcinoma: a population-based study on incidence and survival in the Netherlands since 1993. Eur J Cancer 2013;49(11):2579-86.
[3] Stigliano A, Chiodini I, Giordano R, Faggiano A, Canu L, Della Casa S, et al. Management of adrenocortical carcinoma: a consensus statement of the Italian Society of Endocrinology (SIE). J Endocrinol Invest 2016;39(1):103-21.
[4] Lucon AM, Pereira MA, Mendonça BB, Zerbini MC, Saldanha LB, Arap S. Adrenocortical tumors: results of treatment and study of Weiss’s score as a prognostic factor. Rev Hosp Clínicas 2002;57(6):251-6.
[5] Bharwani N, Rockall AG, Sahdev A, Gueorguiev M, Drake W, Grossman AB, et al. Adrenocortical carcinoma: the range of appearances on CT and MRI. Am J Roentgenol 2011;196(6):W706-14.
[6] Erickson LA. Challenges in surgical pathology of adrenocortical tumours. Histopathology 2018;72(1):82-96.
[7] El-Farhan N, Rees DA, Evans C. Measuring cortisol in serum, urine and saliva - are our assays good enough? Ann Clin Biochem 2017;54(3):308-22.
[8] Fassnacht M, Libé R, Kroiss M, Allolio B. Adrenocortical carcinoma: a clinician’s update. Nat Rev Endocrinol 2011;7(6):323-35.
[9] Ozimek A, Diebold J, Linke R, Heyn J, Hallfeldt K, Mussack T. Bilateral primary adrenal non-Hodgkin’s lymphoma and primary adrenocortical carcinoma - review of the literature preoperative differentiation of adrenal tumors. Endocr J 2008;55(4):625-38.
[10] Puglisi S, Perotti P, Pia A, Reimondo G, Terzolo M. Adrenocortical carcinoma with hypercortisolism. Endocrinol Metab Clin North Am 2018;47(2):395-407.
[11] Fassnacht M, Arlt W, Bancos I, Dralle H, Newell-Price J, Sahdev A, et al. Management of adrenal incidentalomas: European society of endocrinology clinical practice guideline in collaboration with the European network for the study of adrenal tumors. Eur J Endocrinol 2016;175(2):G1-G34.
[12] Else T, Kim AC, Sabolch A, Raymond VM, Kandathil A, Caoili EM, et al. Adrenocortical carcinoma. Endocr Rev 2014;35(2):282-326.
[13] Zhang HM, Perrier ND, Grubbs EG, Sircar K, Ye ZX, Lee JE, et al. CT features and quantification of the characteristics of adrenocortical carcinomas on unenhanced and contrast-enhanced studies. Clin Radiol 2012;67(1):38-46.
[14] Libé R. Adrenocortical carcinoma (ACC): diagnosis, prognosis, and treatment. Front Cell Dev Biol 2015;3:45.
[15] Labelle P, Kyles AE, Farver TB, de Cock HEV. Indicators of malignancy of canine adrenocortical tumors: histopathology and proliferation Index. Vet Pathol 2004;41(5):490-7.
[16] Hoang MP, Ayala AG, Albores-Saavedra J. Oncocytic Adrenocortical carcinoma: a morphologic, immunohistochemical and ultrastructural study of four cases. Mod Pathol 2002;15(9):973-8.
[17] Weissferdt A, Phan A, Suster S, Moran CA. Adrenocortical carcinoma: a comprehensive immunohistochemical study of 40 cases. Appl Immunohistochem Mol Morphol 2014;22(1):24-30.
[18] Weiss LM. Comparative histologic study of 43 metastasizing and nonmetastasizing adrenocortical tumors. Am J Surg Pathol 1984;8(3):163-70.
[19] Beuschlein F, Weigel J, Saeger W, Kroiss M, Wild V, Daffara F, et al. Major prognostic role of ki67 in localized adrenocortical carcinoma after complete resection. J Clin Endocrinol Metab 2015;100(3):841-9.
[20] Miller BS, Gauger PG, Hammer GD, Giordano TJ, Doherty GM. Proposal for modification of the ENSAT staging system for adrenocortical carcinoma using tumor grade. Langenbecks Arch Surg 2010;395(7):955-61.